Most hormone disorders of the adrenal cortex occur in the context of overgrowth or underdevelopment of the adrenal gland. At embryonic stages, the fetal adrenal cortex already has the ability to synthesize and secrete steroid hormones that are critical for fetal development. These functional fetal cortical cells then undergo regression and are replaced by continuously renewing adult-like cortical cells after birth. The continuously renewing adult cortical cells grow from the outermost layer of the cortex and form the ?adult zone?, whereas fetal cortical cells stay in the inner portion of the cortex, losing the steroid synthesis ability overtime and form the ?fetal zone?. During development, the fetal zone (x-zone in mice) regresses while the adult zone grows. However, the mechanisms that regulate the differential development and the regression of the cell layers of the adrenal cortex remain unclear. We have used several unique mouse models to obtain preliminary results that lead to the central hypothesis: thyroid hormone receptor (TR) positive cells, a novel cell population in the adrenal cortex, regulates the remodeling of the adrenal cortical layers. In Aim 1, we will delineate the contribution of this novel identified cell population to adrenal cortical differentiation and remodeling by using our unique knock-in reporter mouse lines for detection of expression TR isoforms. The cell fate of cells in the x-zone will also be investigated by lineage tracing. In Aim 2, we will use next generation sequencing and genome-wide DNA analysis to identify target genes underlying thyroid hormone-mediated remodeling of the adrenal gland. In Aim 3, we will further study the transcriptional function of TR and its co-repressors in the adrenal gland. The proposed study links the function of these two endocrine organs and aims to use thyroid hormone receptor-mediated effects in adrenocortical remodeling as a novel approach to address fundamental questions about the mechanisms that control the differentiation and maintenance of adrenocortical cell layers.